Substituted carbinol derivatives

ABSTRACT

The compounds are steroidal 17-allenyl carbinol derivatives, e.g., 17 Alpha -propadienylestra-4,9-dien-17 Beta -0l-3-one. The compounds have, e.g., progestational activity and are useful in fertility control.

United States Patent 91 Galantay et a1.

[ 1 March 6, 1973 [54] SUBSTITUTED CARBINOL DERIVATIVES [75] lfivni'riEii ii E. csamy,'m5m'stawn; Dietmar A. Habeck, Dover, both of NJ. [73]Assignee: Sandoz-Wander,Inc.,l 1anover,N.J. [22] Filed: sea. 10, 1970[21] Appl. No.: 71,279

Related U.S. Application Data [63] Continuation-impart of Ser. No.778,777, Nov. 25,

1968, abandoned.

[52] U.S. Cl.....260/239.55 C, 260/3974, 260/397.5, 424/243 [51] Int.Cl. ..C07c 169/20, C07c 173/00 [58] Field of Search ..260/397.4, 239.55C; lMachine Searched Steroids [56] References Cited UNITED STATESPATENTS 3,424,768 1/1969 Klimstra ..260/397.5

3,637,771 1/1972 Nedelec et a1 ..260/397.4

3,682,985 8/1972 82500 et a1. ..260/397.4

3,086,027 4/1963 Perelman et a1 ..260/397.3

3,392,166 7/1968 Edwards et a1 ..260/239.55

3,432,528 3/1969 Anner et a1 ..260/397.3

OTHER PUBLICATIONS Vitali et al., Gazz. Chim. 96, 1966, p. 1,126 (pg.1,132 pertinent).

Primary Examiner-Lewis Cotts Assistant ExaminerEthel G. LoveAttorney-Gerald D. Sharkin, Frederick H. Weinfeldt, Robert S. Honor,Walter F. Jewell and Richard E. Vila [5 7] ABSTRACT The compounds aresteroidal l7-allenyl carbinol derivatives, e. g.,17a-propadienylestra-4,9-dien-l 7B- 0l-3-one. The compounds have, e.g.,progestational activity and are useful in fertility control.

1 1 Claims, No Drawings I on n wherein R is alkyl having one to threecarbon atoms,

e.g., methyl, ethyl, n-propyl and isopropyl, and is preferablyunbranched; and

R is a hydrogen atom, methyl, acetoacetyl or lower alkanoyl having twoto four carbon atoms, e.g.,. acetyl, propionyl or butynyl. The processfor preparing the compounds of formula (I) where R H, may be representedby the following reaction scheme A:

Reaction Scheme A (1) Organo-metallo reagent (2) Hydrolysis ComplexHydride reagent wherein R"-has the above stated significance, and eachof R, R" and R' is independently lower alkyl having one to three carbonatoms, e.g., methyl, ethyl and propyl; methyl being preferred, P is aprotected form of rings A, B and C, as indicated below; and Y is halohaving an atomic weight of from 35 to 127 or the residue of a sulfonicacid, e.g., Cl, Br, I, mesylate ion, tosylate ion or the like,preferably I.

The organo metallo reagent (IV) has the composition wherein X is anactive metal or magnesium bromide or iodide, e.g., Li, K, Na, Al/3 Zn/2-MgBr, or M g1, and is prepared by methods disclosed in the literature;and R and R have the above stated significance.

Compound (III) is prepared by treating a corresponding 17-ketosteroid(II) with reagent IV) in a solvent at a temperature of 30 to 100 C.,preferably 20 to C. followed by standard hydrolysis of the resultingadduct in neutral or basic aqueous medium, e.g., water or saturatedammonium chloride solution. The solvent used is dependent upon thecomposition of the organo-metallo reagent. For example, if X is MgBr,'Mgl or Li, the solvent may be ether or tetrahydrofuran, if X is Na, thesolvent may be liquid ammoniaether, liquid ammonia-tetrahydrofuran,dioxane, pyridine or dioxane-pyridine. Particularly advantageous is theuse of X=Li in the presence of complexing amines, e.g., ethylenediamine. This process is represented by step a,. The temperature andsolvent are .not critical.

Compound (V) .is prepared by treating compound (III) with compound (VI)in a solvent such as acetone, etc., at a temperature of 20 to 30 C. Thisis represented by step a,. The temperature and solvent are not critical.

Compound (Ip) is prepared by treating in a solvent compound (V) with acomplex hydride reagent (VII) such as LLAI H at a temperature of 80 to80 C. The solvent may be ether, tetrahydrofuran, pyridine or the like.This is represented by step a Again, neither temperature nor solventsare critical.

The compounds of Formula I where R" is alkanoyl 0 may be obtained usingstandard methods for acylating a tertiary hydroxy group, e.g., by use ofan acylating agent in the presence of a strong acidic catalyst. Forexample, a compound lp may be converted into a Compound l whereR"=OCOCI-I by use of e.g., acetic anhydride in which calcium hydride hadpreviously been dissolved.

The compounds of Formula I where R" is methyl may be obtained in amanner known per se, for instance by treating a compound Ip at atemperature of about 30 to 30 C. with ll.2 equivalents of strong base(e.g., NaNI-I, or KNH, in liquid ammonia or LiCH, in ether) to form al7-0-anion of compound Ip, and treating the latter, inthe same mixture,with 1-50 equivalents of methyl iodide.

Compounds of Formula I wherein R is acetoacetyl are obtainable byreacting a compound of Formula I bearing a l7B-hydroxy group with asuitable reagent, e.g., diketen'e, under conventional conditionsemployed in carrying out such a reaction. For example, a

l 7B-hydroxy bearing compound of Formula I may be reacted with diketenein an inert organic solvent, e.g., benzene or toluene or mixturethereof, in the presence of a small amount of organic tertiary aminebase, e.g., pyridine, at relatively low temperatures, e.g., at fromabout to +35 C.

The disclosure below respecting protective groups pertains as well tothe above described method for methylating and acylating compounds lpand Ill.

Certain compounds of Formula (II) and protected forms thereof are knownand may be prepared by methods disclosed in the literature; and thosecompounds not specifically disclosed may be prepared according toanalogous methods from known materials.

Conventional recovery techniques are utilized for obtaining thecompounds of Formula (I), e.g., crystallization, column or layerchromatography, etc.

The above-mentioned protected forms P of the steroidal compounds includethe structures P1 and P2 emand [O 0 wherein R is lower alkyl, e.g.,being from one to four carbon atoms, such as methyl, ethyl, propyl orbutyl. Deprotection" can be achieved in conventional ways; i.e., with P1and P2, hydrolysis in acid medium followed by conjugation of the doublebonds in acid or basic medium. The above-described protected" forms areadvantageously retained until compound I, where R=H or CH is obtained,which compound may then be deprotected as described above to obtain theunprotected form of a compound I where R=H or CH A compound of formula Iwherein R"=I-I can then be converted if desired to a particular compoundof Formula I where R acyl, by conventional means.

In accordance with an additional aspect of this invention the compoundsof Formula III may be prepared by the following Reaction Scheme B,wherein R, R, R" and P are as defined above.

HO-CHz-N Cu+ bi (VIII) (III) In this scheme, step b is a Mannich-typereaction in- Q volving the ethynyl group in VIII; it can be carried outuncler conditions known to be operative in Mannich reactions of thistype. Preferably, however, step b, is

carried out with geminal amino alcohols of the type In theabove-described procedures, the starting materials and reagents areknown and may be prepared by methods described in the literature, orwhere not known may be prepared in a manner analogous to that forpreparing the known compounds.

The substituted carbinol derivatives represented by formula (I) aboveare useful because they possess pharmacological properties in animals.In particular, such compounds are useful as fertility control agents inmammals as they possess progestational activity as indicated by standardtests, such as the clauberg test, e.g., the method basically describedin Endocrinology 63 (1958) 464 wherein the rabbit is given 0.01 to 1.0milligrams of active agent.

These compounds may be combined with a pharmaceutically acceptablecarrier or adjuvant. They may be administered orally or parenterally.The dosage will vary depending upon the mode of administration utilizedand the particular compound employed. However, in general, satisfactoryresults are obtained when the compounds are administered at a dailydosage of from about 0.01 milligrams to 2 milligrams. This daily dosagemay be given in equally divided doses, e.g., two times a day, or asingle dose, e.g., in sustained release form. It will be appreciated bythose skilled in the art, that the daily dosage level is independent ofbody weight. Dosage forms suitable for internal administration comprisefrom about 0.005 milligrams to about 2 milligrams of the compound inadmixture with a solid I or liquid pharmaceutical carrier or diluent,solid forms being preferred.

The compounds of formula I are also useful as menstrual functionregulating agents. For the above-mentioned uses the compounds of formulaI may be administered alone in the manner and dosage described above, orin combination with a suitable estrogenic agent, the latter for exampleat a dosage of about 0.1 mg. The estrogenic agent may be admixed withthe compound of formula I, or, alternatively, the estrogenic agent maybe administered alone in the first part of the menstrual cycle, and inadmixture with the compound of formula I in the latter days of the cycleof the host, i.e., a higher primate.

A representative formulation suitable for oral ad ministration is atablet prepared by standard tabletting techniques which contains thefollowing:

Ingredients Part by Weight l7alpha-Propadienylestra-4,9-dienl 7beta-ol-3-one .05 Tragacanth 2 Lactose 89.45 5 Corn starch 5 Talcum 3 Magnesiumstearate 0.50

The compound l7alpha-propadienylestra-4,9-dien- 17beta-ol-3-one isparticularly useful as a fertility control agent as it has in additionto its progestational activity, estrogenic activity as well asestrogen-antagonistic activity when administered orally or parenterallyat daily dosages of from about 0.1 milligrams to 0.5 milligrams. It willbe readily appreciated by those skilled in the art that a compoundconcurrently exhibiting the three above-mentioned properties is highlydesirable as it can be used to obtain efficient fertility control atadvantageously low dosage levels and thereby minimizes undesirableside-effects commonly associated with standard fertility control agents,e.g., those which comprise an estrogenic agent with a progestationalagent.

The three above-mentioned activities can be observed in the white rat bystandard test methods; e.g., the progestational activity can bedemonstrated by the rat deciduoma method described by Yochim and DeFeo(Endocrinology 71:134, 1962), the estrogenic activity can bedemonstrated by observation of cornification of vaginal epithelium ofadult female ovariectomized white rats, e.g., by the method of Biggersand Claringbold, and estrogen-antagonistic activity can be demonstratedby observation of inhibition of cornification of vaginal epithelium ofadult ovariectomized female white rats caused by standard estrogens.

This invention is illustrated but not limited by the following examples,wherein all temperatures are Centragrade, and room temperature is 20 toC., unless indicated otherwise.

EXAMPLE 1 l7a-Propadienylestra-4,9-dienl 7fi-ol-3-one STEP 1.

l7a-Dimethylaminopropynyl-3-ethylenedioxyestra- 5(10),9(1l)-dien-17B-ol.

OH CH:

To a Grignard mixture, prepared from 1.50 g. magnesium, 4.68 g. of ethylbromide and ml. tetrahydrofuran, there is dropwise added 5.3 g. ofdimethylaminopropyne, dissolved in 10 ml. of tetrahydrofuran. After theevolution of ethane ceases, a solution of 1.888 g. of3-ethylenedioxyestra-5( l0), 9( l l)-dien-l7-one in 30 ml. oftetrahydrofuran is dropwise added, the temperature being maintained at0-5 C. during the addition and 20-25 for 4 further hours. Aqueous 2 NNaOH solution (100 ml.) is added and the mixture concentrated in vacuoat temperatures not exceeding 30 C. until the total volume is 100 ml.The concentrated mixture is then extracted with ether (5 X 25 ml.),using a centrifuge to facilitate separation from the salt-containingaqueous phase. The product of this step (I) (a,) is obtained byevaporating the dried ethereal solutions and pumping off any excessdimethylaminopropyne present.

of of l7a-Dimethylaminopropynyl-3-ethylenedioxyestra 5( l0),9( l l)-dien-l 7B-ol Methiodide STEP 2 g. ofl7a-dimethylaminopropynyl'3-ethylenedioxyestra-S (10), 9(11)-dien-l7B-ol (product of step 1) is dissolved in 30 ml. of acetone.After addition of 3.2 g. of methyl iodide, the mixture is kept at 8 for18 hours. The title product of this step (2) crystallizes and isisolated by filtration and washing with anhydrous ether.

STEP 3 3-Ethylenedioxy-17a propadienylestra-5(l0), 9(1 l)-dien-17B-ol OH--cH=c=cH,

To a suspension of 2.75 g. of the methiodide of step 2, in 50 ml. oftetrahydrofuran, there is added, at 9.3 ml. of a 0.525 molar lithiumaluminum hydridetetrahydrofuran solution. The mixture is brought to -10where it is stirred until r minutes) a clear solution is obtained.Finally it is kept at room temperature for 12 hours. ml. of 2 N aqueousNaOH solution containing 50 mg. ditert.-butylcresol is added and themixture concentrated in vacuo until the total volume is 100 ml.Extraction with 5 X 20 ml. ether on the centrifuge, drying the etherealsolutions over K CO and evaporation gives the title product, 3-ethylenedioxy- 1 7a-propadienylestra-5( l0), 9( l 1 dien-l 7B-ol.

STEP 4 l7a-Propadienylestra-4,9-dienl 7B-ol-3-one 3 G. of the product ofstep 3, i.e., 3-ethylenedioxyl7a-propadienylestra-5(10),9( ll)-dien-l7B-ol is dissolved in a mixture of 25 ml. of methanol and 0.8ml. of H N aqueous hydrochloric acid and is kept at 30 C. for 30minutes. After dilution with 50 ml. of water, the

product is extracted with methylene chloride (5 X 8 ml.). Evaporation ofthe dried methylene chloride solutions, followed by recrystallization ofthe residue from compound, 17a- EXAMPLE 2l7a-Propadienylestra-4,9-dien-l 7B-ol-3-one STEP 117a-Dimethy1aminopropynyl-3-ethylenedioxyestra- To a solution of 2.5 g.of 3-ethylenedioxy-17aethynylestra-5(l0),9(1l)-dien-17B-o1 in 25 ml. ofdioxane, is added 2.5 ml. of dimethyl-amino methanol, 80 mg. of cuprouschloride and 1.4 ml. of glacial acetic acid. The stirred reactionmixture is then maintained at a temperature of 60 to 70 for 2% hours andthen I cooled and diluted with ice/water containing sufficient sodiumbicarbonate to insure that the solution remains basic. The organicmaterial is extracted with methylene chloride and the solution soobtained dried over sulfate and evaporated. The residue is crystallizedfrom acetone-petroleum ether (b.p.6090); l/l to yield17a-dimethylaminopropynyl-3-ethylenedioxyestra- 5(10),9(l l)-dien-17B-o1, m.p. 161163.

STEP 2 Methiodide Salt To a solution of 2.6 g.l7a-dimethylaminopropynyl-3 -ethylenedioxyestra-5( l),9(l l)-dien-17B-olin 70 ml. of acetone is added 20 ml of methyl iodide. The solution iskept at a temperature of for 18 hours and then the solvent removed andthe residue is crystallized from acetone to yield the product, i.e., themethiodide salt of 17a-dimethylaminopropynyl-3-ethylenedioxyestra- 5(),9(l l )-dien-1 73-01, m.p. 229230.

STEP 3 3-Ethylenedioxy-17a-propadienylestra-5(10),9( 1 1 dien-17B-ol Toa suspension of 3.2 g. of the methiodide salt (prepared in Step 2), in100 ml. of anhydrous tetrahydrofuran under ice cooling is added dropwise16 ml. of a 0.85 M solution of lithium aluminum hydride intetrahydrofuran. The reaction mixture is allowed to warm to roomtemperature and stirred for a total of 1- V2 hours by which timesolution is almost complete. Water is then added under cooling todecompose the excess hydride reagent, and on continued addition ofwater, a solid precipitates. This is isolated and dissolved in methylenedichloride. The organic solution is dried over sodium sulfate andevaporated to yield 3- ethylenedioxy-l7a-propadienylestra-5(10),9(l ldien-l7B-ol.

STEP4 17a-Propadienylestra-4,9-dien-l 7B-ol-3-one Using the product ofStep 3, above and repeating the procedure described in Step 4 ofExamplel, yields the title compound, 17a-propadienyl-estra-4,9-dien-17B-ol-3-one.

EXAMPLE 3 l7a-Dignethylaminopropynyl-ethylenedioxyestra- 5( l0),9( l 1)-dien-1 713-01 A total of 5.2 g. of lithium is added portionwise to 500ml of ethylenediamine stirred and maintained at a temperature of 50-60under nitrogen. After the addition is complete, the resulting bluesolution is heated to for 1 hour when a pale yellow reaction mixture isobtained which is then cooled to 10 and 58 g. of dimethylaminopropyne isadded dropwise over 5 minutes. Stirring is continued at room temperaturefor 1 hour, when a solution of 11 g. of 3-ethylenedioxyestra-5( l0),9( l1 )-dien-l7-one in ml. of tetrahydrofuran is added. The mixture is nowstirred at room temperature for 24 hours. After cooling (icewater),1,000 ml. of saturated aqueous sodium chloride are added and theresulting organic layer is separated. After drying over sodium sulfate,the solvent is removed and the residue is crystallized from acetone/pet.ether, 1] 1 to yield 17adimethylaminopropynyl-3-ethylenedioxyestra-5(l0), 9(11)-dien-17B-ol, m.p. 161-l63.

The thus-obtained intermediate compound may be utilized in the samemanner as the product obtained in Step 1 of Example 2 to obtainl7a-propadienylestra- 4,9-dien-l7B-ol-3-one.

EXAMPLE 4 l 7B-Acetoacetoxy-17a-propadienylestra-4,9-dien-3- one 000CHzCOCHa To a solution of 1.0 g. of 17a-propadienylestra-4,9- dien-l7fi-ol-3-one in a mixture of 18.5 ml. of benzene, 9.25 ml. of tolueneand 0.23 ml. of pyridine, there is dropwise added, at 0, 1.8 ml. ofdiketene, dissolved in 9 ml. of benzene. The mixture is then kept at 25for 3 hours. The product is isolated by washing the mixture withice-cold 0.1 N sodium hydroxide and water, drying over anhydrous sodiumsulfate, evaporating to dryness and purifying the oil thus obtained bychromatoplate techniques (silica gel S development: CHCl MeOH 98/2): [a]=245.0 (C=l, CHCl EXAM PLE 5 l 7B-Acetoxy- 7apropadlenylestra-4,9-dien-3 -one r Ow A mixture of 0.050 g. of calcium hydride in ml. ofacetic anhydride'is refluxed for l hour then 0.5 g. ofl7a-propadienylestra-4,9-dien-l7Bol-3-one is added and refluxingcontinued for 3 more hours. After cooling, the mixture is poured on iceand extracted with methylene chloride. The methylene chloride solutionis washed with aqueous saturated sodium bicarbonate and then water,dried over anhydrous sodium sulfate and evaporated to give the oilyproduct which is further purified by thin layer chromatography on silicagel (chloroform-methanol: 98/2). [a] 233.4 (C=l, CHCI EXAMPLE 6 I7B-Methoxyl 7a-propadienylestra-4,9-dien-3-one OCIIJ CH STEP 13,3-Dimeth0xy-l7a-pr0padienylestra-,5 9(1 1)- dien-l7B-ol.

Repeating Steps 1, 2 and 3 of Example 1, but using 3,3-dimethoxy-17a-ethynylestra-5( 10), 9(1 l)-dienl 7- one in place of the3-ethylenedioxyestra-5(10), 9(1 1 dien-l7-one used therein, there isobtained analogously 3 ,3-dimethoxy-l7d$a-propadienylestra-5(10), 9( ll)-- dienl 7B-ol.

STEP 2 3 ,3 ,l VB-trimethoxyl 7a-propadienylestra-5( l0), 9( l l )-dieneTo a solution of lithium amide in liquid ammonia (prepared from 73.5 mg.Li and 26 ml. of NH there is added a solution of 3.55 g of3,3-dimethoxy-l7apropadienylestra 5 10 9 1 l)-dien-l7B-ol in 50 ml ofether. After 2 hours at refluxing ammonia temperature,

2.5 g of methyl iodide is added and the ammonia allowed to escape.Addition of 50 ml of water and separation of the ether phase (and etherwashup) followed by the evaporation of the dried ethereal solutionsyields the title compound, 3,3,l7B-trimethoxy-l7 a-propadienylestra-5(l0), 9( l l )-diene.

STEP 3 l7B-Methoxy-l 7a-propadienylestra-4,9-dien'3-one Treating theproduct of step 2, above, by the procedure of step 4 of Example 1 yieldsthe title product, l7B-Methoxy-l 7a-propadienylestra-4,9-dien- 3-one.

What is claimed is:

1. A compound of the formula:

OR H

hydrogen atom.

9. A compound of the formula:

wherein R is alkyl having from one to three carbon atoms.

10. The compound of claim 9 wherein R is methyl. 1 1. The compound ofclaim 9 wherein R is ethyl.

* III l UNITED STATES PATENT AND TRADEMARK OFFICE CERTIFICATE OFCORRECTION PATENT NO.

5,719,670 DATED March 6 1973 INVENTOR(S) I EUGENE E. GALANTAY & DIETMARA. HABECK It is certified that error appears in the aboveidentifiedpatent and that said Letters Patent is hereby corrected as shown below:

Column 6, end of line 23, (in the Title of Step 2 of Example 1) delete"STEP".

Column 10, line 40 (second line of claim 7), change "methyl,acetoacetyl"to R Third Day of Mara-M798! [SEA L] Allen:

RENE D. TEGTMEYER Arresting Ojficer Acting Commissioner of Patents andTrademarks

1. A compound of the formula:
 2. A compound of claim 1 wherein Ra ismethyl.
 3. The compound of claim 2 wherein Rb is a hydrogen atom.
 4. Thecompound of claim 2 wherein Rb is acetyl.
 5. The compound of claim 2wherein Rb is acetoacetyl.
 6. The compound of claim 2 wherein Rb ismethyl.
 7. A compound of claim 1 wherein methyl,acetoacetyl is ethyl. 8.The compound of claim 7 wherein Rb is a hydrogen atom.
 9. A compound ofthe formula:
 10. The compound of claim 9 wherein Ra is methyl.